1. Field of the Invention
The disclosed invention relates to compositions and methods for promoting the maturation of monocytes. More specifically, the disclosed invention relates to the treatment of subjects suffering from cancer or infections with one or more monocyte maturation-promoting compounds.
2. Description of the Related Art
Monocytes, macrophages, and dendritic cells are of primary importance in the immune defense system of the body, playing a central role in the induction of the acquired immune response through their capacity to present antigen and regulate the function of T-lymphocytes.
Monocytes are mononuclear phagocytic white blood cells derived from the myeloid stem cells. Monocytes circulate in the blood stream and then move into tissues, at which point they mature into macrophages. Monocytes and macrophages are one of the first lines of defense in the immune process. Mononuclear phagocytes function as accessory cells in the recognition and activation phases of adaptive immune responses. Their main functions are to display antigens in a form that can be recognized by T lymphocytes and to produce membrane and secreted proteins that serve as secondary signals for T cell activation. Some mononuclear phagocytes may differentiate into dendritic cells, which play important roles in the induction of T lymphocyte responses to protein antigens.
During development, circulating monocytes migrate into essentially all body organs to form macrophages where they show highly heterogeneous phenotypes and functions based on tissue localization. During the immune process, signals are delivered to the bone marrow which promote the proliferation and release of promonocytes into the circulation where they are known as monocytes.
Numerous compounds such as colony stimulating factors and certain cytokines have been shown to regulate the development of mononuclear phagocytes. Granulocyte-macrophage colony-stimulating factor (GM-CSF), for example, is a cytokine which induces the differentiation, proliferation, and activation of a variety of immunologically active cell populations. GM-CSF facilitates the development of cell-mediated immunity, and recent studies suggest that a critical event in this action of GM-CSF is to induce the differentiation of monocytes into dendritic cells, which are potent antigen-presenting cells (Bell, D. et al., Adv Immunol, 72:255-324 (1999); Avigan, D., Blood Rev., 13:51-64 (2000)).
Because of the potency of compounds such as GM-CSF as immune adjuvants, particular interest has focused on their use to overcome the poor immunological response associated with cancer and chronic infections (for review, see Lawson, D., and Kirkwood, J. M., J. Clin. Oncol., 18:1603-1605 (2000)). For example, treatment with GM-CSF has been proposed to protect a substantial fraction of patients with high-risk malignant melanoma against relapse and death. In a study by Spitlier and co-workers, the median survival time of GM-CSF-treated melanoma patients (with stage III or stage IV disease) was increased by a factor of three as compared with that of matched control patients (Spitlier et al., J Clin. Oncol., 18:1614-1621).
Despite these results, there is a need for improvement of monocyte maturation-promoting therapy in the treatment of neoplastic disease and chronic infections.
The disclosed invention relates to compositions and methods for promoting the maturation of monocytes. In one embodiment, a method for promoting the maturation of monocytes is provided. A composition including a reactive oxygen species (ROS) inhibiting or scavenging compound and a monocyte maturation-promoting agent are co-administered to target a plurality of monocytes to promote monocyte maturation. The monocyte maturation-promoting agent can include Interleukin-1 (IL-1), granulocyte-macrophage colony-stimulating factor (GM-CSF), Interleukin-3 (IL-3), Interleukin-4 (IL-4), Interleukin-6 (IL-6), TNF-xcex1, granulocyte colony-stimulating factor (G-CSF), macrophage colony-stimulating factor (M-CSF), Interleukin-12 (IL-12), Interleukin-15 (IL-15), or Interleukin-18 (IL-18). The monocyte maturation-promoting agent can be administered alone or in combination with a vaccine, a plurality of antigen, or an adjuvant. The ROS inhibiting compound may include histamine and/or histamine related compounds such as histamine dihydrochloride, histamine phosphate, and histamine receptor agonists. A hydrogen peroxide or ROS scavenging compound such as catalase, glutathione peroxidase or ascorbate peroxidase can also be administered in combination with a monocyte maturation-promoting agent to facilitate the development of monocytes to dendritic cells.
Advantageously, the method of promoting monocyte maturation is accomplished by administering a ROS inhibiting compound and at least one monocyte maturation-promoting agent in vivo. The administration of the monocyte maturation-promoting agent and ROS inhibiting or scavenging compound can be performed simultaneously. Alternatively, the administration of the ROS inhibiting compound may be completed within 24 hours of the administration of the monocyte maturation-promoting agent.
In another aspect of the invention, the ROS inhibitor or scavenger is administered in a dose of from about 0.1 to about 20 mg/day. Preferably, the ROS inhibitor or scavenger is administered in a dose of from about 0.5 to about 8 mg/day. Even more preferably, the amount of ROS inhibitor or scavenger is from about 1 to about 6 mg/day. Advantageously, the monocyte maturation-promoting agent is administered in the dosage of from about 500 to about 1,000,000 U/kg/day; more preferably, the amount is from about 1,000 to about 500,000 U/kg/day; and even more preferably, the amount of monocyte maturation-promoting agent administered is from about 3,000 to about 200,000 U/kg/day.
In another embodiment, a method of augmenting the activity of a monocyte maturation enhancing agent is provided. The method includes administering a ROS inhibitor or scavenger in a pharmaceutically acceptable form and the monocyte maturation enhancing agent, whereby the monocyte maturation effects of the agent are augmented. Preferably, the monocyte maturation enhancing agent is at least one cytokine. More preferably, the cytokine is Interleukin-1 (IL-1), granulocyte-macrophage colony-stimulating factor (GM-CSF), Interleukin-3 (IL-3), Interleukin-4 (IL-4), Interleukin-6 (IL-6), TNF-xcex1, granulocyte colony-stimulating factor (G-CSF), macrophage colony-stimulating factor (M-CSF), Interleukin-12 (IL-12), Interleukin-15 (IL-15), or Interleukin-18 (IL-18). The monocyte maturation-promoting agent can be administered alone or in combination with a vaccine, a plurality of antigen, or an adjuvant. Most preferably, the cytokine is GM-CSF.
Advantageously, the cytokine is administered in the dosage of from about 500 to about 1,000,000 U/kg/day; more preferably, the amount is from about 1,000 to about 500,000 U/kg/day; and even more preferably, the amount of cytokine administered is from about 3,000 to about 200,000 U/kg/day. The ROS inhibitor or scavenger may be administered in a dose of from about 0.1 to about 10 mg/day. Preferably, the ROS inhibitor or scavenger is administered in a dose of from about 0.5 to about 8 mg/day. Even more preferably, the amount of ROS inhibitor or scavenger is from about 1 to about 5 mg/day.
Another aspect of the disclosed invention further contemplates a method of treating a subject having a neoplastic disease with a ROS inhibitor or scavenger and a monocyte maturation-promoting agent. The method includes identifying a subject having a neoplastic disease, administering a ROS inhibitor or scavenger in a pharmaceutically acceptable form, and simultaneously administering the monocyte maturation-promoting agent. Alternatively, the monocyte maturation-promoting agent can be administered to a subject after a stable concentration of ROS inhibitor or scavenger is achieved. The monocyte maturation-promoting agent may be a cytokine such as IL-1, GM-CSF, IL-3, IL-4, IL-6, TNF-xcex1, G-CSF, M-CSF, IL-12, IL-15, or IL-18. Advantageously, the monocyte maturation-promoting agent is administered in a dose of from about 500 to about 1,000,000 U/kg/day; more preferably, the amount is from about 1,000 to about 500,000 U/kg/day; and even more preferably, the amount of monocyte maturation-promoting agent is administered is from about 3,000 to about 200,000 U/kg/day.
In another embodiment, a method of treating a subject having a chronic infection is provided. The method includes identifying a subject suffering from a chronic infection, administering a ROS inhibitor or scavenger in a pharmaceutically acceptable form, and administering at least one monocyte maturation-promoting agent, wherein the monocyte maturation-promoting agent facilitates the maturation of monocytes to dendritic cells. The monocyte maturation-promoting agent and ROS inhibitor or scavenger can be added simultaneously. Alternatively, the monocyte maturation-promoting agent can be added after a stable concentration of ROS inhibitor or scavenger is achieved. In a preferred embodiment, the monocyte maturation-promoting agent is a cytokine selected from the group consisting of IL-1, GM-CSF, IL-3, IL-4, IL-6, TNF-xcex1, G-CSF, M-CSF, IL-12, IL-15, and IL-18.
The chronic infection can be caused by a virus. The virus can be an adenovirus, cytomegalovirus, Epstein-Barr virus, herpes simplex virus 1, herpes simplex virus 2, human herpesvirus 6, varicella-zoster virus, hepatitis B virus, hepatitis D virus, papilloma virus, parvovirus B19, polyomavirus BK, polyomavirus JC, hepatitis C virus, measles virus, rubella virus, human immunodeficiency virus (HIV), human T cell leukemia virus I, or human T cell leukemia virus II.
Alternatively, the chronic infection can be caused by a parasite. The parasite can include species of Leishmania, Toxoplasma, Trypanosoma, Plasmodium, Schistosoma, or Encephalitozoon. 
A pharmaceutical composition including a compound effective to promote the maturation of monocytes and a ROS inhibitor or scavenger combined in a single pharmaceutically acceptable carrier is similarly provided. The compound effective to promote the maturation of monocytes may include IL-1, GM-CSF, IL-3, IL-4, IL-6, TNF-xcex1, G-CSF, M-CSF, IL-12, IL-15, or IL-18. Preferably, the compound effective to promote the maturation of monocytes is GM-CSF.
In still another embodiment, a method of manufacture of a pharmaceutical composition including providing a ROS inhibitor or scavenger and at least one monocyte maturation-promoting compound in a pharmaceutically acceptable form is disclosed. Preferably, the monocyte maturation-promoting compound includes IL-1, GM-CSF, IL-3, IL-4, IL-6, TNF-xcex1, G-CSF, M-CSF, IL-12, IL-15, or IL-18. More preferably, the monocyte maturation-promoting compound is GM-CSF.